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the Democratic Republic of the Congo, 1976-2014. Elife, 4. ISSN
2050-084X DOI: 10.7554/eLife.09015
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RESEARCH ARTICLE
elifesciences.org
Ebola virus disease in the Democratic
Republic of the Congo, 1976-2014
Alicia Rosello1,2*†, Mathias Mossoko3†, Stefan Flasche4, Albert Jan Van Hoek4,
Placide Mbala5, Anton Camacho4, Sebastian Funk4, Adam Kucharski4,
Benoit Kebela Ilunga3, W John Edmunds4, Peter Piot4, Marc Baguelin1,4*,
Jean-Jacques Muyembe Tamfum5
Public Health England, London, United Kingdom; 2University College London,
London, United Kingdom; 3Direction de lutte contre la maladie, République
Démocratique du Congo Ministére de la santé Publique, Kinshasa, Democratic
Republic of the Congo; 4London School of Hygiene and Tropical Medicine, London,
United Kingdom; 5Institut National de Recherche Biomédicale, Kinshasa, Democratic
Republic of the Congo
1
*For correspondence:
[email protected] (AR);
[email protected] (MB)
Abstract The Democratic Republic of the Congo has experienced the most outbreaks of Ebola
virus disease since the virus’ discovery in 1976. This article provides for the first time a description
and a line list for all outbreaks in this country, comprising 996 cases. Compared to patients over 15
years old, the odds of dying were significantly lower in patients aged 5 to 15 and higher in children
under five (with 100% mortality in those under 2 years old). The odds of dying increased by 11% per
day that a patient was not hospitalised. Outbreaks with an initially high reproduction number, R (>3),
were rapidly brought under control, whilst outbreaks with a lower initial R caused longer and
generally larger outbreaks. These findings can inform the choice of target age groups for
interventions and highlight the importance of both reducing the delay between symptom onset and
hospitalisation and rapid national and international response.
DOI: 10.7554/eLife.09015.001
†
These authors contributed
equally to this work
Competing interests: The
authors declare that no
competing interests exist.
Funding: See page 13
Received: 27 May 2015
Accepted: 01 October 2015
Published: 03 November 2015
Reviewing editor: Quarraisha
Abdool Karim, University of
KwaZulu Natal, South Africa
Copyright Rosello et al. This
article is distributed under the
terms of the Creative Commons
Attribution License, which
permits unrestricted use and
redistribution provided that the
original author and source are
credited.
Introduction
Ebola virus disease (EVD) outbreaks are rare and knowledge of the transmission and clinical features
of this disease is sparse. As of May 2015, the devastating outbreak in West Africa has resulted in more
than ten times the number of cases reported in all previous outbreaks and will ultimately provide
improved insights into EVD. Here, for the first time, all the databases from EVD outbreaks in the
Democratic Republic of the Congo (DRC) have been cleaned and compiled into one anonymised
individual-level dataset (See Supplementary file 1). The data provided are an invaluable addition to
the West Africa data and will allow a more complete picture of the disease. The DRC is the country
that has experienced the most outbreaks of EVD. Since the virus’ discovery in 1976, there have been
six major outbreaks (Yambuku 1976, Kikwit 1995, Mweka 2007, Mweka 2008/2009, Isiro 2012, and
Boende 2014) and one minor outbreak (Tandala 1977) reported in the DRC, four in the northern
Equateur and Orientale provinces and three in the southern provinces of Bandundu and KasaiOccidental (Figure 1). Some of these have been described in the literature (World Health
Organization, 1978; Heymann et al., 1980; Khan et al., 1999; Muyembe-Tamfum et al., 1999,
2012; Maganga et al., 2014). However, the individual-level data and corresponding lessons from
these outbreaks have not been collated or made publicly available; by doing so, we aim to permit a
more powerful statistical analysis and a fuller understanding of the disease. The end of the most
recent outbreak in the DRC was declared on the 21st of November 2014. This provides an
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eLife digest Ebola virus disease commonly causes symptoms such as high fever, vomiting, and
diarrhoea. It may also cause muscle pain, headaches, and bleeding, and often leads to death.
There have been seven outbreaks of Ebola virus disease in the Democratic Republic of the Congo
(DRC) since 1976. The DRC is the country that has had the most outbreaks of this disease in the
world. The most recent outbreak in the DRC was in 2014; this was separate from the outbreak that
started in West Africa in the same year. Rosello, Mossoko et al. have now compiled the data from all
seven of the outbreaks in the DRC into a single dataset, which covers almost 1000 patients.
Analysing this data revealed that people between 25 and 64 years of age were most likely to be
infected by the Ebola virus, possibly because most healthcare workers fall into this category. Age
also affected how likely a patient was to die, with those aged under 5 and over 15 more likely to die
than those aged between 5 and 15. Delaying going to hospital once symptoms had started, even by
one day, also increased the likelihood of death.
Rosello, Mossoko et al. also examined the Ebola virus effective reproduction number, which
indicates how many people, on average, an infected person passes the virus on to. Outbreaks that
initially featured viruses with a reproduction number larger than three tended to be stemmed
quickly. However, when the reproduction number was lower, national and international organisations
were slower to respond to the signs of the outbreak, leading to outbreaks that lasted longer.
Further research is needed to understand why the likelihood of death is different for different age
groups and to investigate the effect of the different routes of transmission of the virus on
interventions such as vaccination.
DOI: 10.7554/eLife.09015.002
unparalleled opportunity to assemble all the information gathered about EVD in the DRC through
almost four decades, learn from the Congolese experience with this disease, and compare the
features of EVD in DRC with the epidemic that has had such a devastating effect in West Africa.
Results
During the last 38 years, 1052 cases of EVD have been reported in the DRC, of which 996 are reported
in this dataset. The geographical context, historical timeline, and main characteristics of these
outbreaks are depicted in Figure 1 and Table 1. A detailed account of the outbreaks can be found in
Appendix 1, Section B. The early accounts of all outbreaks except for Mweka 2007 involved a
healthcare facility. The direct epidemiological link between index cases (when known) and animal
reservoirs has not been found for any of the outbreaks. The lack of systematic surveillance together
with the presence of diseases with similar symptoms allows EVD cases to go unnoticed for long
periods of time. A repository of the interventions that led to the control of the outbreaks is outlined in
Supplementary file 2. Table 2 summarises the number of cases and deaths reported in each
outbreak.
Case demographics
The number of cases and case-fatality ratios (CFRs) varied greatly between outbreaks (Table 2). It can
also be observed that laboratory confirmation became more readily available over time. Across all
outbreaks, 57% of cases were female (95% CI = 53.9–60.1). In the second Mweka outbreak and in the
Isiro outbreak, more than 70% of cases were females. However, in the other outbreaks, the
percentage of females was lower (53–59%). When comparing the probable and confirmed cases by
age with the overall DRC population (Figure 2), we observed a high concentration of cases in the
25–64 age category compared to the baseline population. This might be because at this age
individuals are more likely to be carers. The occupation was only recorded during three outbreaks:
Kikwit, Boende and Isiro. During Kikwit, 23% (73/317) of cases were known healthcare workers (HCWs)
and 0.6% (2/317) were possible HCWs. During Boende, the occupation was recorded for 85% (58/68)
of cases. 14% (8) were known HCWs and 3% (2) were possible HCWs. During Isiro, occupation was
reported for 94% (49/52) of cases. 27% (13) were HCW. Although occupation was not recorded on an
individual level, during Yambuku, 13 of the 17 Yambuku Hospital workers contracted EVD (World
Health Organization, 1978).
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Figure 1. Map and historical timeline of the EVD outbreaks in the DRC. (A) Map of the Democratic Republic of the
Congo (DRC) where the area of the circles are proportional to the number of cases (probable and confirmed) per
outbreak. (B) The outbreaks (in orange) and relevant wars (in purple) are positioned in time.
DOI: 10.7554/eLife.09015.003
Epidemic curves
The epidemic curves were plotted for the six major outbreaks (Figure 3). The date of infection was based
on symptom onset when available (701/995). When it was not, hospitalisation dates were used (5/995). In
cases where these were also absent (281/995), the notification dates were used as proxy. For Mweka 2007,
the date of infection was mostly based on the notification date (98%), whereas in the other outbreaks,
infection dates refer to onset of symptoms almost exclusively (>90%). In time, case definitions became
more specific. With the exception of Kikwit, in which notification and the closure of healthcare facilities
coincided closely in time, outbreaks seemed to peak before major interventions were initiated.
Symptoms
The proportion of probable and confirmed cases reporting EVD symptoms is shown in Figure 4.
Overall, the most commonly reported symptom was fever, which was reported by 95% of cases (95%
CI = 92.6–97.3%) and at least 90% of cases in every outbreak. Reports of vomiting were also similarly
common across all major outbreaks, reported by 75% of cases (95% CI = 69.3–79.2) and between 57%
and 76% of cases for all major outbreaks. There was considerable variation in how frequently the
remaining symptoms were reported for different outbreaks. In particular, hemorrhagic symptoms
were present in 61% (95% CI = 51–71) of cases during Kikwit but only 10% (95% CI = 5–18) during
Mweka 2007. The Bundibugyo ebolavirus (Isiro outbreak) did not present a symptom profile that was
particularly different from that seen for the Zaire ebolavirus (all other outbreaks). However, this was
difficult to conclude given the large variation between outbreaks.
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Table 1. Main characteristics of the outbreaks
Mweka
07
Yambuku
Tandala
Isiro
Boende
Ecosystem
Tropical rain
forest
Rainforest/ Urban/peri-urban
savannah
Forested Forested savannah
savannah
Tropical area of
savannah scattered
with gallery forests
Tropical rainforest
Inhabitants
Small villages
<500 residents
Small
village
Villages and city of
200,000
170,000
170,000
700,000 exposed
250,000 in Boende
but most cases living
in small villages
Start
Aug-76
End
Oct-76
Jun-76
Jan-95
Apr-07
Nov-08
Jun-12
Aug-12
Jun-76
Jun-95
Oct-07
Jan-09
Nov-12
Oct-12
Healthcare facility Yambuku Catholic –
involved in history Mission Hospital
Kikwit II Maternity
Unit and Kikwit
General Hospital
–
Kaluamba health
centre, injections
clandestine nurse
from Kaluamba
Chemin de Fer des
Uélé clinic (Isiro),
Isiro General
Reference Hospital
Antenatal care in her
village, Miracle
centre in Isaka,
Lokolia health centre
Index case
detected?
Possible: charcoal
maker who worked
in the forest
No
No
No
No
No
No
Kikwit
Mweka 08/09
DOI: 10.7554/eLife.09015.004
CFRs
The mean CFR overall was 79% (95% CI = 76.4–81.6), but there were significant differences between
epidemics and within epidemics over time (Figure 5 and Figure 5—figure supplement 1). The
highest average CFR was seen during the first outbreak in Yambuku (mean = 96%, 95% CI = 92.6–97.9
in our subset of 262/318 cases). Kikwit, Mweka 2007, and Boende had high average CFRs ranging
from 74% to 78%. During the Isiro and Mweka 2008 outbreaks, the CFR was lower, at 54 and 44%
(95% CI = 39.5–67.8 and 26.4–62.3), respectively.
All EVD patients under 2 years of age died (N = 29, Figure 5—figure supplement 1). CFRs
generally decreased during childhood and then increased again to plateau at around 70–80% in
adulthood (Figure 5—figure supplement 2). This pattern was less readily observed for the CFRs in
the Yambuku outbreak, which remained high and similar for all ages.
Table 2. Distribution of cases and deaths by type and overall case-fatality ratios per outbreak
Yambuku (1976) Kikwit (1995) Mweka (2007) Mweka (2008/9) Isiro (2012) Boende (2014) All outbreaks
Cases (n)
Suspected
–
–
–
–
0
2
2
Probable
–
317
–
22
16
28
383
Confirmed
–
–
24
10
36
38
108
Total
318*
317
264
32
52
68
733
Suspected
–
–
–
–
0
0
0
Probable
–
–
–
12
15
28
55
Confirmed
–
–
17
2
13
21
53
Total
280*
248
187
14
28
49
526
88*
78 (73–83)
74 (68–79)
44 (26–62)
54 (39–68)
74 (62–84)
79 (76–82)
54 (48–59)
55 (48–61)
72 (53–86)
77 (63–87)
53 (40–65)
57 (54–60)
Deaths (n)
Case-fatality ratio
(%, 95% CI)
Sex
(% Female, 95% CI) 59 (53–65)
Where the distinction between probable, confirmed, and suspected cases was available, the case-fatality ratio and % female were calculated with only
probable and confirmed cases. Only cases for which outcomes were reported were included in the case-fatality ratio denominator.
*The values presented in this table for Yambuku were taken from the literature, as our data are a subset of the total cases during the outbreak (262/318).
DOI: 10.7554/eLife.09015.005
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Figure 2. Incidence of cases by age and sex in the DRC outbreaks in comparison to the demographics of the
national 1975–2010 population.
DOI: 10.7554/eLife.09015.006
In the regression model that included the delay between symptom onset and hospitalisation as a
factor but excluded three outbreaks for missing data (Table 3), the baseline CFR in individuals over 15
years of age during the first month of an EVD outbreak who were admitted to hospital after 0.3 days
(the average time from symptom onset to admission to hospital) during the Boende outbreak was 74%
(95% CI = 17.8–99.3). The CFR was similar during the Isiro outbreak but was significantly higher during
the Kikwit outbreak (94%). The CFR in 0–5 year olds was 76%, and in 5–15 year olds, it was significantly
lower at 36%. The odds of dying declined on average by 31% (95% CI = 3.1–52.0%) each month after
the start of an outbreak and increased by 11% (95% CI = 1.8–20.7%) per day that a symptomatic
person is not hospitalised (Table 3).
In the regression model that included all major outbreaks, the CFR for individuals over 15 years of
age during the first month of the outbreak during the Boende outbreak was estimated at 79% (95% CI
= 25.8–99.5). The Yambuku, Kikwit, and Mweka 2007 outbreaks had significantly higher CFRs (96%,
94% and 93%) and the Mweka 2008 outbreak had a significantly lower CFR (48%). 0–5 year olds had
significantly higher CFRs (90%) than those over 15 years of age. For the 5–15 year olds, the CFR was
significantly lower (57%). The odds of dying declined on average by 35% (95% CI = 22.6–45.9) each
month after the start of each outbreak (Table 4).
Reproduction numbers through time
Changes in the effective reproduction number, R, over the course of the outbreaks were plotted in
Figure 6. In Yambuku, Mweka 2008, and Boende 2014, R dropped below one within 3–5 weeks after
the initial case and the outbreak was rapidly brought under control. In these settings, the spread of
EVD during the first 2 weeks had been high (R > 3). By contrast, in Kikwit 1995, Mweka 2007, and Isiro
2012, where the initial transmission rate was lower, spread of EVD was sustained for more than 13
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Figure 3. Time course of the EVD outbreaks in DRC. Confirmed cases are plotted in red, probable cases in orange,
suspected in light blue, cases that were either suspected or probable cases in dark blue, and cases for whom the
definition was unknown in purple. The dashed lines represent important events that occurred during the outbreaks
(in orange, the first records of the disease, in red, the first notifications, and in black, important interventions carried
out). For Yambuku, this was the closure of Yambuku Mission Hospital; for Kikwit, the closure of all hospitals, health
centres, and laboratories in the area; for Mweka 2007, the opening of two mobile laboratories; for Mweka 2008, the
opening of the first isolation centre; for Isiro, first the opening of the isolation centre and later the opening of the
laboratory; and for Boende, the opening of the first isolation centre. Notification dates were when the cases were
first notified to the Direction de Lutte contre la Maladie (DLM).
DOI: 10.7554/eLife.09015.007
weeks. Overall, we can see that R declines before the major interventions occurred, which could point
to behavioural changes that occurred spontaneously in the populations.
Delays in case detection
The delay distributions from onset of symptoms to notification, from onset of symptoms to
hospitalisation, from onset of symptoms to death, length of hospital stay, and from hospitalisation
to death were plotted for each outbreak (when available) in Figure 7. The largest delays between
symptom onset to notification and to hospitalisation were seen during the Kikwit outbreak (12.9
days and 5.0 days, respectively). The largest delay between symptom onset and death and the
longest duration of hospitalisation were seen during the Isiro outbreak (11.4 and 8.0 days,
respectively). However, this was only recorded for the Kikwit, Mweka 2008, and Isiro outbreaks. The
longest delay between hospitalisation and death was observed during the Mweka 2008 outbreak
(11.0 days) (Table 5).
Discussion
This article provides for the first time a description and a line list for all outbreaks that have occurred in
the DRC. This represents almost 40 years of surveillance data, seven outbreaks, and 996 suspected,
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Figure 4. Percentage of probable and confirmed cases with abdominal pain, diarrhoea, fever, haemorrhagic
symptoms, headache, and vomiting. These were calculated by dividing the number of probable and confirmed
cases with symptoms by the number of probable and confirmed cases with symptoms, no symptoms, and blanks for
cases for who the presence or absence of at least one symptom was reported. Note that the majority of cases in the
Mweka 2007 outbreak were diagnosed a posteriori using recorded symptoms.
DOI: 10.7554/eLife.09015.008
probable, or confirmed cases. It is an invaluable resource for studying the epidemiology and clinical
features of EVD. We highlight the importance of reducing the delay between symptom onset and
hospitalisation, as the odds of dying increase by 11% per day that a patient is not hospitalised. We
also observe higher incidence in those between 25 and 64 years of age and a higher CFR in patients
under 5 or over 15 years of age than in those between 5 and 15 years old. These trends mirror those
observed during the West African outbreak, where cumulative incidence was highest in those
between 16 and 44 years of age and CFR progressively dropped from 89.5% in those under 1 year of
age to 52.1% in those between 10 and 15 years, to rise again to 78.7% in those over 45 years old
(WHO Ebola Response Team et al., 2015a). These distinctions could inform the choice of target age
groups for interventions such as vaccination.
Another important finding is that during outbreaks with an initially lower reproduction number, R,
(≤3) national and international response was slower, outbreaks took longer to control, and (with the
exception of Yambuku, where the virus was first discovered) were larger outbreaks than those with
initially high R. This occurred during the current outbreak in West Africa, where the basic reproduction
numbers for Guinea, Sierra Leone, and Liberia have been estimated at 1.51, 2.53, and 1.59,
respectively, and indicates the need for any future EVD to be met with rapid national and international
response (Althaus, 2014).
Our estimates largely coincide with those recently reviewed in the literature (Van Kerkhove et al.,
2015). The basic reproduction numbers reported for the Kikwit outbreak (3.00) is comprised in the
range found by other studies (1.36–3.65) (Chowell et al., 2004; Ferrari et al., 2005; Lekone and
Finkenstädt, 2006; Legrand et al., 2007; Forsberg White and Pagano, 2008; Ndanguza et al., 2011),
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Figure 5. Evolving case-fatality ratios with time after the start of the outbreak. Monthly point estimates are
presented with 95% binomial confidence intervals. The dashed horizontal line indicates the average case-fatality
ratio (CFR) during each outbreak. The vertical dashed lines represent important events that occurred during the
outbreaks (in red, the first notifications, and in black, important interventions carried out). For Yambuku, this was the
closure of Yambuku Mission Hospital; for Kikwit, the closure of all hospitals, health centres, and laboratories; for
Mweka 2007, the opening of two mobile laboratories; for Mweka 2008, the opening of the first isolation centre; for
Isiro, first the opening of the isolation centre and later the opening of the laboratory; and for Boende, the opening of
the first isolation centre. Notification dates were when the cases were first notified to the DLM.
DOI: 10.7554/eLife.09015.009
The following figure supplements are available for figure 5:
Figure supplement 1. CFR by age groups for each outbreak.
DOI: 10.7554/eLife.09015.010
Figure supplement 2. Aggregated CFRs for all outbreaks by age group.
DOI: 10.7554/eLife.09015.011
and our estimate for the Yambuku outbreak (5.00) is similar to that reported by Camacho et al.
(4.71, range = 3.92–5.66) (Camacho et al., 2014). The mean delay of onset of symptoms to
hospitalisation and to death estimated here for Kikwit (5.0 and 9.5, respectively) was also similar to
that found by other authors (4–5 [Khan et al., 1999; Rowe et al., 1999] and 9.6–10.1 [Bwaka et al.,
1999; Khan et al., 1999]). Our estimated mean delay of onset of symptoms to death during the
Boende outbreak (9.4) was slightly lower than that found by other authors (11.3) but included in
their reported range (1–30) (Maganga et al., 2014). The delay between hospitalisation and death
during the Kikwit outbreak found in the literature (4.6) coincided with our estimate (4.5) (Khan et al.,
1999). In addition, our estimates of the overall CFR for Kikwit and Boende (78% and 74%,
respectively) coincided with other estimates reported in the literature (74–81% [Muyembe and
Kipasa, 1995; Khan et al., 1999; Ndambi et al., 1999; Sadek et al., 1999; Chowell et al., 2004]
and 74% [Maganga et al., 2014], respectively). The remaining outbreak estimates have not been
studied by other authors and are reported here for the first time.
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Overall, CFRs and delays between symptom
onset and hospitalisation, symptom onset and
OR 2.50% 97.50%
death, and hospitalisation and death reported in
Outbreak Isiro 2012
0.89 0.31
2.59
our study do not differ substantially with those
Outbreak Kikwit 1995
5.44 1.43
21.87
reported for the current outbreak (WHO Ebola
Response Team et al., 2015b). The data
Age [0, 5)
1.12 0.23
6.63
presented were originally collected for the
Age [5, 15)
0.2 0.05
0.7
containment of the outbreaks rather than for
Months since first case
0.69 0.48
0.97
providing the basis of an epidemiological study
Delay onset to hospitalisation 1.11 1.02
1.21
of the disease. As such, variables are not
EVD, Ebola virus disease.
recorded consistently across all outbreaks and
Estimated through binomial regression with age group
there are missing data. This dataset does not
and year of outbreak as factorial covariates and the
take into consideration undetected cases. A
number of months since the start of the outbreak and
surveillance study carried out in northwestern
the delay from symptom onset to hospitalisation as
DRC between 1981 and 1985, through clinical
continuous covariates.
records and serological testing, detected 21
DOI: 10.7554/eLife.09015.012
cases likely to be EVD, suggesting that sporadic
cases do occur (Jezek et al., 1999). Another
serosurvey carried out in Yambuku after the
outbreak suggested that that 17% of the population in the village was infected asymptomatically
(Breman et al., 1978). Under-reporting may differ between and during outbreaks and may impact the
calculated estimates such as CFRs, which limits the validity of direct comparisons of values between
outbreaks. Other limitations include the different case definitions employed in different outbreaks and
that the method used to calculate the effective reproduction numbers is susceptible to changes in
reporting during the outbreak (as most methods are). However, it is robust if the extent of
underreporting remains constant during each outbreak. Moreover, it is robust to different reporting
sensitivity between outbreaks.
The regular re-emergence of EVD in human hosts is likely to be connected to the presence of the virus in
animal reservoirs, such as bats and monkeys (Leroy et al., 2009; Muyembe-Tamfum et al., 2012). The
presence of vast tropical rainforests covering entire regions of the DRC and the strong link existing between
local economies and the forest makes a re-emergence of the virus in the country in the near future very likely
(Pigott et al., 2014). Although the Mweka 2007 outbreak has been linked to the consumption of fruit bats
that migrate to the area (Leroy et al., 2000), the epidemiological link between index cases (when known)
and animal reservoirs has not been found for any of these outbreaks.
All outbreaks except for the 2007 Mweka outbreak have involved hospital transmission during the
early part of the outbreak, illustrating the amplifying effect that poor infection control can have on
EVD epidemics. A study of the 1976 outbreak has
highlighted the importance of community infection to transmission (Camacho et al., 2014).
Table 4. Odds of dying from EVD
Traditional burials are an important mechanism
Covariates
OR 2.50% 97.50%
of transmission of EVD. Funeral data can help
Outbreak Isiro 2012
0.67 0.29
1.55
inform mathematical models that explore the
Outbreak Kikwit 1995
4.63 1.96
10.94
importance of this route of transmission and can
Outbreak Mweka 2007
3.83 1.61
9.18
help guide resource allocation. This will be
explored in subsequent analysis.
Outbreak Mweka 2008
0.25 0.1
0.63
Mweka 2008 was the shortest and smallest
Outbreak Yambuku 1976 7.11 3.13
16.75
outbreak with the lowest CFR. This could be due
Age [0, 5)
2.49 1.12
6.34
to the short delay between the first notification
Age [5, 15)
0.36 0.21
0.63
and the opening of the isolation centre (10 days).
Months since first case
0.65 0.54
0.77
The low CFR during Isiro could be due to
infection by a less virulent type of virus
EVD, Ebola virus disease.
(B. ebolavirus) and is in line with what has been
Estimated through binomial regression with age group
reported for this virus in other outbreaks
and year of outbreak as factorial covariates and the
(Van Kerkhove et al., 2015).
number of months since the start of the outbreak as
continuous covariate.
In most outbreaks, major interventions arrived
DOI: 10.7554/eLife.09015.013
when the reproduction number, R, was less than
Table 3. Odds of dying from EVD
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Figure 6. Evolving effective reproduction numbers with time after the start of the outbreak and adjusted weekly
incidence. Weekly point estimates of the effective reproduction numbers are presented with 95% confidence
intervals. The dashed horizontal line indicates the threshold R = 1. The vertical dashed lines represent important
events that occurred during the outbreaks (in red, the first notifications, and in black, important interventions carried
out). For Yambuku, this was the closure of Yambuku Mission Hospital; for Kikwit, the closure of all hospitals, health
centres, and laboratories; for Mweka 2007, the opening of two mobile laboratories; for Mweka 2008, the opening of
the first isolation centre; for Isiro, first the opening of the isolation centre and later the opening of the laboratory;
and for Boende, the opening of the first isolation centre. The light grey bars represent the weekly incidence of Ebola
virus disease (EVD) (omitting suspected cases) rescaled by dividing by seven.
DOI: 10.7554/eLife.09015.014
one and the epidemic was already under control. This suggests an important role of other factors,
such as changes in contact behaviour, in shaping the changes of R. For example, there is evidence that
an increase in the proportion of patients admitted to hospital was associated with a reduction in the
size of EVD transmission chains in Guinea in 2014 (Faye et al., 2015) and the community acceptance
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Figure 7. Delay distributions for the EVD outbreaks in the DRC. The bars represent the observed frequency distributions of the delay from onset of
symptoms to notification, onset of symptoms to hospitalisation, onset of symptoms to death, length of hospitalisation, and date of hospitalisation to
death. Delays were censored at 30 days. The red line represents the respective fit of a gamma distribution.
DOI: 10.7554/eLife.09015.015
of EVD control measures in West Africa improved dramatically over the course of the epidemic, which
led to better infection control (Dhillon and Kelly, 2015).
The Boende outbreak began whilst the West African outbreak was gaining international
importance. This much smaller outbreak, with an initial R of five, which consisted of 68 cases, lasted
only 10 weeks. The more remote setting, a background antibody presence in the area and a greater
preparedness to EVD (that led to its notification 3 weeks after the first case and the opening of the
first isolation centre a month later) could have contributed to the avoidance of a larger outbreak
(Heymann et al., 1980; Busico et al., 1999; Maganga et al., 2014).
The high number of EVD cases between 25 and 64 years of age compared to the background
demographics, the high CFR in children under five, the decrease in CFRs in those 5 to 15, and the
subsequent increase in CFR during adulthood are phenomena that warrant further investigation. The
variation in symptoms reported during different outbreaks is also a matter for further research.
Materials and methods
Data
Line list data and reports for each outbreak were retrieved from the Direction de Lutte contre la
Maladie (DLM) (Ministère de la Santé Publique (Direction de la Lutte contre la Maladie), 2007,
2009, 2012; Ministère de la Santé Publique (Comité National de Coordination), 2014). The DLM is
Rosello et al. eLife 2015;4:e09015. DOI: 10.7554/eLife.09015
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Table 5. Mean values and standard deviations
corresponding to the delay distributions
Outbreak
Delay
Mean SD
1995 Kikwit
Onset to notification
12.91
7.72
1995 Kikwit
Onset to hospitalisation
5.02
3.91
1995 Kikwit
Onset to death
9.47
4.44
1995 Kikwit
Length of hospital stay
5.72
5.67
1995 Kikwit
Hospitalisation to death
4.5
3.69
2007 Mweka
Onset to notification
0
0
2008 Mweka
Onset to notification
10.04
8.47
2008 Mweka
Onset to hospitalisation
0
0
2008 Mweka
Onset to death
7.62
4.44
2008 Mweka
Length of hospital stay
1.5
2.12
2008 Mweka
Hospitalisation to death
11
9.85
2012 Isiro
Onset to notification
8.83
8.29
2012 Isiro
Onset to hospitalisation
4
3.27
2012 Isiro
Onset to death
11.37
5.41
2012 Isiro
Length of hospital stay
8
6.56
2012 Isiro
Hospitalisation to death
7.59
5.52
2014 Boende
Onset to notification
6.23
5.08
the public body in charge of containing EVD
outbreaks in the DRC. These data were designed
for outbreak containment rather than for epidemiological analysis; therefore, appropriate cleaning was undertaken. The fields selected were
age, sex, date of symptom onset, date of
hospitalisation, date of hospital discharge, outcome, case definition, date of notification (when
the case was first reported to the DLM), date of
death, occupation, fever, diarrhoea, abdominal
pain, headache, vomiting, hiccups, and hemorrhagic symptoms. Where this information was not
available, it was left blank. A unique ID was
assigned to each patient in the dataset. The
Tandala outbreak (1977) included only one
reported case; therefore, only the context and
history of this outbreak was analysed. We included 262 of the 318 cases reported in Yambuku
(those for which these data were available).
The aggregated line lists can be found in
Supplementary file 1.
Case definitions
According to the WHO EVD case definitions for
outbreak settings; suspected cases are all indi2014 Boende Onset to death
9.39
5.67
viduals (alive or dead) who had a fever and had
2014 Boende Hospitalisation to death 4.86
4.23
contact with a suspected, probable, or confirmed
EVD case or a sick or dead animal; any individual
Delays distributions (delay from onset of symptoms to
notification, onset of symptoms to hospitalisation, onset with a fever and more than three additional EVD
symptoms; or any person with unexplained
of symptoms to death, length of hospitalisation and
date of hospitalisation to death).
bleeding or whose death is unexplained (World
DOI: 10.7554/eLife.09015.016
Health Organization, 2014). Probable cases are
suspected cases that have a clear epidemiological link with a confirmed case. Confirmed cases
are individuals who were tested positive via PCR. In the DRC setting, the case definitions employed
varied somewhat between outbreaks (Appendix 1, Section A). Unless stated otherwise, where the
case definitions distinguished susceptible cases from probable and confirmed cases, all estimates
presented (CFRs, symptom delays, and reproduction numbers) were computed omitting suspected
cases.
2014 Boende
Onset to hospitalisation
4.95
3.32
Patient demographics, epidemic curves, and symptoms
DRC national demographics between 1975 and 2010 were used as reported by the UN Department of
Economic and Social Affairs (United Nations (Department of Economic and Social Affairs), 2013).
For temporal comparison of patient reports, we used the date of infection. When available, we used
the date of symptom onset. When these were unavailable, hospitalisation dates were used instead. If
these were also absent, the notification dates were used as proxy.
When calculating the proportion of confirmed and probable cases that presented with EVD
symptoms, we assumed that patients for whom the presence or absence of at least one symptom was
reported did not display any additional symptoms unless those were also reported.
CFRs, reproduction numbers, and delay distributions
The odds of dying from EVD were estimated through binomial regression with age group and year of
outbreak as factorial covariates and the number of months since the start of the outbreak and the
delay from symptom onset to hospitalisation as continuous covariates. The age groups used were 0–5
years, 5–15 years, and >15 years. The delay from symptom onset to hospitalisation was present for
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63% of probable or confirmed cases. These dates were not recorded for Yambuku and Mweka 2007
and only for four cases for Mweka 2008. For this reason, these outbreaks were excluded from this first
analysis. A second regression model was conducted that excluded the delays from symptom onset to
hospitalisation as an explanatory variable, enabling the use of data from all major outbreaks and
increasing statistical power. The start of an outbreak was defined by the earliest onset of symptoms of
any detected case. The CIs were calculated using profiled log-likelihood.
We calculated the weekly effective R, the average number of individuals that were infected by a
typical EVD case during the period of infectiousness, by reconstructing the transmission tree of each
outbreak on the basis of date of infection for each case (Wallinga and Teunis, 2004). To link a case to
its most likely source, we assumed a serial interval of 15.3 days with a standard deviation of 9.3 days as
reported during the current outbreak in West Africa (Maganga et al., 2014). Delays in care were only
calculated for those outbreaks for which the necessary dates were recorded.
Software
R-3.1.2 was used for the cleaning, analysis, and plotting of figures (R Development Core Team,
2011).
Ethical approval
This study was approved by the LSHTM Research Ethics Committee (approval number PR/1541/1541).
Role of the funding source
The funders had no role in the design, collection, analysis, and interpretation of data, or in the writing
of the manuscript. The corresponding authors had full access to all the data and were responsible for
the final decision to submit for publication.
Acknowledgements
This study was funded by the Fischer Family Trust, the National Institute for Health Research Health
Protection Research Unit in Immunisation at the London School of Hygiene and Tropical Medicine in
partnership with Public Health England, the Research for Health in Humanitarian Crises Programme
(managed by Research for Humanitarian Assistance, Grant 13165). The views expressed are those of
the authors and not necessarily those of the funders. We’d like to thank all the community nurses and
volunteers on the ground that collaborated with the DLM to collect this data amid challenging
circumstances.
Additional information
Funding
Funder
Grant reference
Author
Fischer Family Trust
Alicia Rosello, Mathias
Mossoko, Placide Mbala, Marc
Baguelin, Jean-Jacques
Muyembe Tamfum
National Institute for Health
EPIDZD03
Research Health Protection
Research Unit in Immunisation
at the London School of
Hygiene and Tropical
Medicine in partnership with
Public Health England
Albert Jan Van Hoek, Marc
Baguelin
Research for Health in
Humanitarian Crises
Stefan Flasche, Anton
Camacho, Sebastian Funk,
Adam Kucharski
13165
The funders had no role in study design, data collection and interpretation, or the
decision to submit the work for publication.
Rosello et al. eLife 2015;4:e09015. DOI: 10.7554/eLife.09015
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Author contributions
AR, MB, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or
revising the article; MM, PM, BKI, Acquisition of data, Drafting or revising the article; SF, AJVH, AC,
SF, AK, Analysis and interpretation of data, Drafting or revising the article; WJE, PP, J-JMT,
Conception and design, Analysis and interpretation of data, Drafting or revising the article
Ethics
Human subjects: This study was approved by the LSHTM Research Ethics Committee (approval
number PR/1541/1541). Informed consent and consent to publish were not required as the data had
no personally identifiable information.
Additional files
Supplementary files
Supplementary file 1. Aggregated line list for all outbreaks in the Democratic Republic of the
Congo.
·
·
DOI: 10.7554/eLife.09015.017
Supplementary file 2. Repository of the interventions carried out during all outbreaks in the
Democratic Republic of the Congo.
DOI: 10.7554/eLife.09015.018
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Appendix 1
Section A. Case definitions for the different outbreaks
Yambuku 1976 case definitions
Suspected
All those presenting with headache and/or fever for at least 24 hr that had contact with a
probable or confirmed case within the previous 21 days.
Probable
Person living in the epidemic area who died after one or more days with two or more of the
symptoms (headache, fever, abdominal pain, nausea and/or vomiting, and bleeding). The
patient must have within the prior 21 days received an injection or had contact with a probable
or confirmed case and the illness must not have any other obvious cause.
Confirmed
Ebola virus isolated, demonstrated by electron microscopy or IFA titre of at least 1:64 within 21
days after symptom onset.
Kikwit 1995 case definitions
Probable
• Fever+ contact with Ebola virus disease (EVD) case.
OR
• Fever AND at least 3 symptoms (headache, vomiting/nausea, anorexia, diarrhoea, fatigue,
abdominal pain, myalgia, generalized generalised joint pains, dysphagia, hiccups).
OR
• Any unexplained death.
Clinical cases
All those presenting hemorrhagic symptoms.
Mweka 2007, Mweka 2008/2009, and Isiro 2012 case definitions
Suspected
• All those (dead or alive) presenting with fever that had contact with a patient suffering from a
hemorrhagic fever or any sickly live or dead animal.
OR
• All those (dead or alive) presenting with fever and any three of the following symptoms:
Headache
Vomiting
Anorexia/loss of appetite
Diarrhoea
Intense fatigue
Abdominal pain
Muscular or joint pain
Difficulty swallowing
Difficulty breathing
Hiccups
OR
• Any unexplained bleeding.
OR
• Any unexplained death.
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Probable
• Suspected case evaluated by a clinician.
OR
• Deceased case with an epidemiological link to a confirmed case.
OR
• Suspected case that is known to have travelled in an area affected by the outbreak.
Confirmed
Suspected or probable case that has been tested positive in the laboratory.
Boende 2014 case definitions
Suspected
• All those (dead or alive) presenting or having presented with a sudden-onset high fever that
had contact with a suspected, probable or confirmed EVD case or any sickly live or dead animal.
OR
• All those (dead or alive) presenting or having presented with a sudden-onset high fever of
sudden onset and any three of the following symptoms:
Headache
Vomiting
Anorexia/loss of appetite
Diarrhoea
Intense fatigue
Abdominal pain
Muscular or joint pain
Difficulty swallowing
Difficulty breathing
Hiccups
OR
• Any unexplained bleeding.
OR
• Any unexplained sudden death.
Probable
All suspected cases that cannot be confirmed biologically but have an epidemiological link with
a confirmed case (as determined by the surveillance committee).
Confirmed
Suspected or probable cases with a positive result in the laboratory (presence of Ebola antigen,
presence of viral RNA detected by PCR or presence of anti-Ebola IgM).
Non-case
All suspected cases with a negative laboratory result (no Ebola antigen, no RNA by PCR, and no
specific anti-Ebola IgM detected).
Section B. Description of the outbreaks
Yambuku, 1976
The first known case was a 44-year-old male teacher who fell ill after a trip near Gbadolite and
was admitted at the Yambuku Catholic Mission Hospital on the 26th of August 1976 with a
febrile illness thought to be malaria/typhoid fever. He later developed gastrointestinal bleeding
and died on the 8th of September. The hospital held 120 beds and was run by 17 medical staff
including three Belgian nuns. Five syringes and needles were provided to the hospital
outpatient workers every morning and these were re-used on different patients without
appropriate sterilisation. Parenteral injection was the main delivery method for the majority of
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the medication administered to patients in the hospital, including vitamins given to pregnant
women, and greatly contributed to the spread of disease through this population. On the 30th
of September, the Yambuku Mission Hospital was closed and the Ebola virus (Z. ebolavirus) was
isolated on the 13th of October. Between the 1st of September and the 24th of October, 318
cases and 280 deaths were reported (World Health Organization, 1978).
Tandala, 1977
The following year, in June 1977, a 9-year-old girl presented to the Tandala Mission Hospital
also in the Equateur province, approximately 300 km west from Yambuku. She died of an acute
hemorrhagic fever, later recognised as EVD (Heymann et al., 1980).
Kikwit, 1995
In 1995, cases of EVD were reported in the city of Kikwit, the most densely populated area
affected by EVD in the Democratic Republic of the Congo (DRC) to date, and home at the time
to 200,000 residents (Khan et al., 1999; Muyembe-Tamfum et al., 1999). The index case was
thought to be a charcoal maker who worked in the forest close to Kikwit. The first cases were
observed in early April at the Kikwit II Maternity Hospital. After a laboratory technician from this
facility was transferred to Kikwit General Hospital and underwent two laparotomies for a
suspected perforated bowel, two nurses assisting the procedure and several providing postoperative care became ill. At the end of April, an outbreak of bloody diarrhoea was reported in
the Kikwit General Hospital. Initially, shigellosis was suspected, but upon receipt of laboratory
supplies sent from Kinshasa, patient samples were tested and this hypothesis was discarded.
Blood from 14 acutely ill and convalescent patients was collected on the 4th of May and sent for
testing to the CDC, Atlanta. All hospitals, health centres, and laboratories in the Kikwit area
were closed. Patients were quarantined at the Kikwit General Hospital with no running water,
electricity, nor latrines. One physician and three nurses volunteered to stay with the patients.
On the 10th of May, the CDC confirmed the EVD diagnosis. The quarantine of patients in the
Kikwit General Hospital had limited success because food had to be provided by patients’
relatives. In addition, due to the poor living conditions, many patients fled the hospital
(Muyembe-Tamfum et al., 1999). Between the 13th of January and the end of June, 317 cases
and 248 deaths were reported.
Mweka, 2007
The first cases of EVD during the Mweka outbreak in 2007 were detected in the Mweka, Bulape,
and Luebo health zones of the Kasai Occidental province. The Mweka health zone alone spans
over 20,000 km and comprises over 170,000 inhabitants. These cases were initially attributed to
a novel disease originally named the Kampungu syndrome, a hybrid between typhoid fever,
shigellosis, and Ebola. However, it was later recognised that three separate outbreaks of these
diseases were co-existing in the same location. The retrospective nature of the diagnosis
hindered the epidemiological investigation. From April to October, 264 cases and 187 deaths
were reported. However, only 24 cases were confirmed. Two international mobile laboratories
were opened on the 27th of September, one in Mweka (Public Health Agency of Canada,
PHAC) and one in Luebo (CDC) (Ministère de la Santé Publique (Direction de la Lutte contre
la Maladie), 2007). This outbreak was later associated with the consumption of fruit bats that
annually migrate in masses to the area (Leroy et al., 2009).
Mweka, 2008/2009
One year later, a new outbreak of EVD was detected in the same area. The epicentre of the
outbreak was Kaluamba (Mweka) but the outbreak spread into the neighbouring district of
Luebo. The first reported case was an 18-year-old mother who had been suffering from fever
since the 15th of November and was hospitalized at the Kaluamba health centre on the 27th.
She died from a post-partum haemorrhage after giving birth to a premature 6-month-old baby
who died the same day. A traditional burial was then conducted. Several of her contacts
including the nurse that saw her at the health centre developed EVD. The epidemiologists
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conducting the investigation postulated that she could have been infected though the
injections she had received from the 4th to the 11th of November by a clandestine nurse from
Kaluamba in an attempt to decrease her fever. This clandestine nurse had previously treated
another patient who had died 2 weeks before. Between the 18th and the 25th of December,
national and international support arrived on site and MSF Belgium volunteers opened the first
isolation centre in Kaluamba on the 27th of December. On the 2nd of January, the isolation
centre was transferred from Kaluamba to Kampungu, where new cases were being reported
and MSF had built an isolation centre during the preceding outbreak with greater capacity (25
patients). Three mobile laboratories were opened on the 15th of January (Ministère de la
Santé Publique (Direction de la Lutte contre la Maladie), 2009). In total, from November to
January, 32 cases and 14 deaths were reported.
Isiro, 2012
On the 12th of July 2012, an EVD outbreak was declared in the Kibaale region of Uganda, east
of the Albert Lake. On the other side of this lake lies the Orientale province of the DRC. Due to
the proximity to the outbreak, the DRC reinforced EVD surveillance in this region. On the 2nd of
August, the first suspected cases were reported in the Isiro and Dungu health zones in the
Haut-Uélé (a population estimated at 700,000), making this the first known cross-border
epidemic. Already in June, seven HCWs had died at the Chemin de Fer des Uélé clinic (Isiro)
from a gastrointestinal febrile illness. When, in July, a daughter and her mother (who was caring
for her) at the Isiro General Reference Hospital presented with a similar illness with additional
hemorrhagic symptoms, samples were sent to the CDC’s Uganda Virus Research Institute
laboratory in Entebbe. The diagnosis of EVD was confirmed on the 16th of July. This time, the
infecting pathogen was the B. ebolavirus, different from the Z. ebolavirus, encountered in all
other outbreaks in the DRC. On the 6th of August, a treatment centre was established at the
Isiro General Reference Hospital that was re-organised by MSF Belgium and Spain who arrived
on site on the 10th of August. On the 25th of August, the first laboratory was installed. The last
case was confirmed on the 11th of October and the outbreak was declared over on the 24th of
November. In total, 52 cases and 28 deaths were reported (Ministère de la Santé Publique
(Direction de la Lutte contre la Maladie), 2012).
Boende, 2014
The last outbreak to date took place 2 years later in the Boende health zone in the Djera sector
(Equateur province), which comprises approximately 250,000 inhabitants. In mid-August 2014, a
set of suspiciously grouped cases and deaths were reported by the military personnel of the
Watsi-Kengo camp to the central government. A 34-year-old pregnant woman from the
Ikanamongo village who was receiving antenatal care in her village started to develop a fever in
the first week of August. She was transferred to the Miracle centre in Isaka but died a few hours
after her arrival. Because it is traditional not to burry a heavily pregnant mother with her child
still inside her, a post-mortem cesarean section was carried out. All the HCWs participating in
the procedure later died of EVD. Days before these events, the nurse designated to the Lokolia
health centre had reported cases of a disease resembling Ebola to the Central Bureau but was
told to keep quiet about his suspicions. On the 18th of August, the health area supervisor
reported similar findings to that of the military to the Direction de Lutte contre la Maladie
(DLM). Eight blood samples were collected from patients hospitalised in Lokolia and WatsiKengo and sent to the INRB, Kinshasa. Six were found positive to Z. ebolavirus. The outbreak
was officially declared over on the 21st of (Ministère de la Santé Publique (Comité National
de Coordination), 2014). 68 cases and 49 deaths were reported.
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